Pre-eclampsia/eclampsia (PE/E) is the most common and serious disorder of human pregnancy and is associated with substantial maternal and perinatal morbidity and mortality. There is currently no known prevention or cure for PE/E with the only effective treatment being Caesarean section, irrespective of gestation. Worldwide, the condition occurs in all major ethnic groups and eclampsia alone is responsible for over 70,000 maternal deaths annually. An assessment of its global economic importance is difficult, if not impossible. In the U.S. a conservative cost estimate in relation to caring for mothers and neonates born of mothers suffering from PE runs into several billions of dollars per annum. Like many other common human diseases there is a large genetic component underlying susceptibility to developing PE/E but the genetics are complex and not yet understood. Several groups, including ours, have provided strong evidence for PE/E susceptibility loci on chromosome 2. In the proposed next phase of the study, we will test hypotheses about the specific genes at the chromosome 2 locus we have identified to be responsible for susceptibility. The overall goal of the research is to identify the specific genes responsible for susceptibility to PE/E and to characterize the functional variants within these genes. Molecular advances in DNA sequencing and quantitative assessments of gene expression, combined with recent development of novel statistical genetic analysis make this a time of unprecedented opportunity for finding the most likely functional variants influencing susceptibility to PE/E. In this project, we will use an innovative combination of state of the science molecular and statistical genetic approaches to identify genetic determinants of susceptibility to this pregnancy disorder that persists as a major global health concern.